The success in treating most diseases mainly is governed by optimizing the rate of drug release and its delivery to the site of action. Diseases that cause pain are typical cases where the rate of drug release has a direct impact on patient health and patient quality of life. For example, while immediate drug release is required to treat fever, migraine headache, or acute dental pain, a controlled release of the same medicine would be a better choice for patients with chronic inflammatory diseases, such as rheumatoid arthritis and osteoarthritis.
Naproxen, (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid and d-2-(6-methoxy-2-naphthyl)propionic acid, is one of the most effective agents in the management of acute and chronic pain and inflammatory diseases. Pharmacologically, naproxen is classified as a non-steroidal anti-inflammatory drug (NSAID). Naproxen has powerful anti-inflammatory, analgesic, and antipyretic properties.
Naproxen is used effectively in treating symptoms of rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendinitis, bursitis, and acute gout. Pain associated with menstrual periods, migraine headaches, and other types of mild to moderate pain also is alleviated by naproxen. Due to the efficacy and toxicity profiles of naproxen, solid and liquid naproxen delivery systems are used to satisfy a wide range of medical needs.
Naproxen can be delivered in immediate release dosage forms by enhancing the rate of dissolution via solubilization, complexation, particle size reduction, or solid dispersion techniques, whereas controlled release forms have been formulated using lipid or polymeric matrix techniques.
For immediate release dosage forms, improved water solubility of the poorly water-soluble naproxen free acid has been achieved by forming solid potassium or sodium salts. Other solid salts of naproxen with water-soluble basic compounds such as lysine (see, e.g., U.S. Pat. No. 4,593,044) or N-(2-hydroxyethyl)pyrrolidine (see, e.g., U.S. Pat. No. 5,206,262) have been described. These techniques provide solid salts with high water solubility; however, these techniques introduce unnecessary electrolytes or diminish the drug solubility in other commonly used, less hydrophilic solvents, such those used to manufacture soft gelatin capsules.
Solubilization techniques to prepare naproxen liquid solutions have been achieved using surfactants (see, e.g., U.S. Pat. No. 4,944,949) or by using surfactant-like salts of organic acids (see, e.g., U.S. Pat. No. 6,383,515). These methods, however, cannot be used in formulating tablets or powder filled capsules.
U.S. Pat. No. 5,854,226 solubilized naproxen as part of solid inclusion complexes with different cyclodextrins. However, the need to use large amounts of cyclodextrin (which can reach up to 50% of the drug concentration) and the concern of cyclodextrin toxicity make it impractical to use this approach with a high-dose drug, such as naproxen.
Particle size reduction to the nano-scale, along with alkalis and a polymeric stabilizer, also results in improved naproxen solubility (see, e.g., U.S. Pat. No. 6,165,506). However, nano-sized drug particles inherently are unstable and tend to aggregate to reduce the high surface energy generated during size reduction.
In view of the foregoing limitations of naproxen formulations, there remains a need for oral naproxen products with higher drug concentrations, as well as methods of manufacturing the oral naproxen products.